1. Field of the Invention
The present invention relates to a process for preparing cyclobutane-1,2-dicarboxylic esters (I) by [2+2]-cycloaddition of ketene acetals and fumaric or maleic esters.
The compounds preparable according to the invention are of the general formula: ##STR2## In this formula, R.sup.1 is a C.sub.1-8 -alkyl group, an optionally substituted mono- or bicyclic cycloaliphatic group having 3 to 10 ring carbon atoms, an optionally substituted aryl or arylalkyl group or an optionally substituted saturated heterocyclic group and R.sup.2 is C.sub.1-4 -alkyl or both radicals R.sup.2 together are --(CH.sub.2).sub.n -- where n is 2 to 4.
Here and below, C.sub.1-4 - or C.sub.1-8 -alkyl groups are in each case all straight-chain or branched primary, secondary or tertiary alkyl groups having 1 to 4 and 1 to 8 carbon and tert-butyl and C.sub.1-8 -alkyl additionally includes, for example, pentyl, isopentyl, neopentyl, hexyl or octyl. Mono- or bicyclic cycloaliphatic groups having 3 to 10 carbon atoms are, for example, groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornan-x-yl, norcaran-x-yl or norpinan-x-yl, where the "x" represents any position of attachment desired. These groups can also carry one or more substituents, for example, C.sub.1-4 -alkyl groups. These substituted cycloaliphatic groups include, for example, menthan-x-yl, bornan-x-yl, caran-x-yl, pinan-x-yl or thujan-x-yl. Aryl groups are aromatic hydrocarbon radicals having one or more rings, i.e., for example, phenyl, x-naphthyl, anthracen-x-yl, phenanthren-x-yl, fluoren-x-yl or biphenyl-x-yl. The rings in radicals having a plurality of rings can also be partially hydrogenated, such as, tetrahydronaphthalen-x-yl, indan-x-yl or acenaphthen-x-yl. Examples of arylalkyl groups include benzyl, 1-phenylethyl, 2-phenylethyl (phenethyl) or diphenylmethyl (benzhydryl). Saturated heterocyclic groups include, for example, tetrahydrofuryl or tetrahydropyranyl. These aryl, arylalkyl or saturated heterocyclic groups can optionally carry one or more identical or different substituents, such as, C.sub.1-4 -alkyl groups or halogen atoms, for example.
The compounds which are preparable according to the invention, in particular those having trans configuration at the cyclobutane ring, are intermediates in the synthesis of pharmaceutically active compounds, for example, of antiviral nucleoside analogues (European Published Patent Application No. 0458643).
2. Background Art
It is known that 3,3-dialkoxycyclobutane-1,2-dicarboxylic esters can be prepared from fumaric or maleic esters and ketene acetals by [2+2]-cycloaddition. Since the cycloaddition proceeds in a stereospecific manner, fumaric esters give products having trans configuration at the cyclobutane ring, usually in the form of a racemate. Furthermore, it is known that if esters of fumaric acid in combination with optically active alcohols are employed, mixtures of diastereomers are obtained in which one of the two stereoisomers [depending on the nature and the configuration of the alcohol component either that having (1S) or that having (1R) configuration at the cyclobutane ring] prevails [European Published Patent Application No. 0458643, Example 1; S. Ahmad, Tetrahedron Lett., (1991), 32, 6997-7000]. The process requires the use of at least two equivalents of dialkylaluminium chloride. A further disadvantage of this process consists in the fact that it has to be carried out at low temperatures of, for example, -75.degree. C. to obtain good yields. On an industrial scale, however, such low temperatures can only be achieved at considerable cost.